1. Field of the Invention
The present invention relates to new and improved inhibitors of Dipeptidyl-Peptidase-IV (DPP-IV) with beta blocker activity, and new and improved treatment methods and related uses. The inhibitors according to the invention are useful for treating and detecting a wide variety of diseases and other abnormal conditions, including diseases impacting the central nervous system.
2. Description of the Background
Dipeptidyl-peptidase-IV (DPP-IV, EC 3.4.14.5) is a protein that, in humans, is encoded by the DPP4 gene. The protein is an antigenic enzyme expressed on the surface of most cell types and is associated with immune regulation, signal transduction and apoptosis. More specifically it is a membrane-anchored aminopeptidase involved in the release of N-terminal dipeptides from proteins and other types or forms of peptides. The enzyme is a type II membrane serine peptidase, and has a substrate preference for proteins or peptides which carry a proline at the penultimate position of their N-termini. The peptide bonds before and after a proline residue is relatively resistant to cleavage by common proteases. It has been speculated that the presence of proline at the penultimate position of the peptide chain—a feature shared by a number of immunopeptides, neuropeptides, and peptide hormones—protects such peptides from degradation by unspecific exopeptidases. A physiological role for DPP-IV would be in the activation, inactivation, or degradation of its substrates through the specific release of a proline-containing dipeptide from the N-terminal region of the substrate peptide.
DPP-IV has been found in the kidney, epithelial cells, endothelial cells, small intestine, prostate, brain, placenta, and liver. In T-cells, it has been shown to be identical to the memory cell surface antigen CD26. Other proteins which display DPP-IV-like activity include fibroblast-activation protein (FAP), an inducible type-II cell-surface glycoprotein selectively expressed by reactive stromal fibroblasts of epithelial cancers and healing wounds [Niedermeyer, et al., Eur. J. Biochem. 1998 254 (1998):650-4] and attractin/mahogany protein, which exists in membrane-bound and secreted forms and is implicated in control of pigmentation, energy metabolism, and CNS myelination [Tang et al., Proc. Natl. Acad. Sci. U.S.A. 97 (2000) 6025-30.].
DPP-IV activity has also been found in serum, urine, seminal plasma, and amniotic fluid. It has been speculated that this soluble DPP-IV activity can be attributed to cleavage of the membrane-bound form of DPP-IV and release of its catalytic portion into the bloodstream [Augustyns, K., et al., Current Medicinal Chemistry, 6 (1999) 311-327]. Additionally, a distinct form of DPP-IV, which appears to be a breakdown product of the T-cell surface antigen DPPT-L, has been described in human plasma. [Duke-Cohan, et al., J. Immunol. 156 (1996) 1714-21].
The physiological roles of DPP-IV have not been completely elucidated. It has been thought that DPP-IV plays a role, amongst others, in the regulation of fat intake, natriuresis, nociception, T-cell activation, regulation of blood glucose, and regulation of the digestive tract. DPP-IV has been implicated in disease states such as HIV infection, diabetes, arthritis and certain cancers. For example, DPP-IV activity and/or expression was found to be elevated in prostate [Wilson, et al., J Androl. 21 (2000) 220-6], colon [Fric, et al., Eur. J. Cancer Prev. 9 (2000):265-8], skin [Van den Oord, Br. J. Dermatol. 138 (1998) 615-21] and lung cancer [Sedo, et al., J Cancer Res. Clin. Oncol. 117 (1991) 249-53], and elevated DPP-IV also has been found in patients having benign prostate hyperplasia. A high activity of DPP-IV is also associated with membrane vesicles found in human, bovine, and equine ejaculate, where it is thought to play a role in the regulation of sperm motility and viability [Minelli A, et al., J Reprod. Fertil. 114 (1998) 237-43; Agrawal, et al., J Reprod. Fertil. 79 (1987) 409-19; Arienti, et al., FEBS Lett. 410 (1997) 343-6].
DPP-IV also is being investigated for its role in type II diabetes because the glucagon-like peptide (GLP-1) can be a substrate for DPP-IV cleavage, and some DPP-IV inhibitors have demonstrated efficacy in animal models of diabetes. Additionally, DPP-IV has been implicated in HIV infection due to its association with CD 26.
High levels of DPP-IV expression have been reported for skin fibroblasts from human patients suffering from psoriasis, rheumatoid arthritis, and lichen planus [Raynaud, et al., J Cell Physiol. 151 (1992) 378]. Inhibition of DPP-IV has been shown to increase release of TGF-beta, a protein having neuroprotective properties. DPP-IV inhibition itself has been implicated in cellular mechanisms relating to neurodegeneration [see PCT publication WO 01/34594].
It follows from the above that inhibitors of DPP-IV may be useful as pharmaceuticals in the treatment of a range of medical conditions. In particular, they may be useful as immunosuppressants, anti-inflammatory agents, drugs that suppress tumor invasion and metastasis formation, drugs that inhibit HIV infectivity, regulators of blood glucose levels in patients suffering from diabetes, agents that affect sperm motility and viability useful both for contraception and in the reproduction of livestock, drugs for the treatment of dermatological disorders such as psoriasis, and as pharmaceuticals for the treatment of neurological disorder.
DPP-IV inhibition has been studied in the treatment of autoimmune diseases such as diabetes, arthritis and multiple sclerosis. See PCT publications WO 97/40832 and WO 98/19998. Additionally, PCT publication WO 94/03055 discusses increasing production of hematopoietic cells with DPP-IV inhibitors. PCT publication WO 95/11689 discloses the use of DPP IV inhibitors to block the entry of HIV into cells. U.S. Pat. No. 5,543,396 discloses the use of inhibitors (certain prolinephosphonate derivatives) to treat tumor invasion. PCT publication WO 95/34538 mentions the use of certain serine protease inhibitors (such as certain DPP-IV and PEP inhibitors) to treat inflammation-related neurological/autoimmune diseases like multiple sclerosis. Efficacy in experimental models of inflammatory disorders has also been described for compounds with DPP-IV inhibitory activity, suggesting that such compounds may be useful in the treatment of medical conditions such as rheumatoid arthritis and inflammatory bowel disorder. Augustyns et al. (Curr. Med. Chem. 6 (1999) 311-327) and Hildebrandt et al. (Clinical Science 99 (2000) 93-104) review the wide therapeutic potential of various classes of DPP-IV inhibitors. Oral DPP-IV inhibitors have been found to improve glucose-dependent insulin secretion and reduce inappropriate glucagon secretion. [Rosenstock et al, “Dipeptidyl peptidase-4 inhibitors and the management of type 2 diabetes mellitus”, Curr Opin Endocrinol Diabetes Obes 14 (2): 98-107 (April 2007)].
DPP-IV inhibitors based upon molecules that bear a resemblance to proline have been investigated in the field. For example, PCT publication WO 95/11689 discloses alpha-amino boronic acid analogs of proline. PCT publication WO 98/19998 discloses N-substituted 2-cyanopyrrolidines as DPP-IV inhibitors. PCT publication WO 95/34538 discloses various proline containing compounds and phosphonate derivatives thereof. Prolinephosphonate derivatives as inhibitors of DPP-IV are also disclosed in U.S. Pat. No. 5,543,396. U.S. Pat. No. 6,172,081 discloses a series of tetrahydroisoquinoline 3-carboxaminde derivatives with potent DPP-W inhibitory activity; U.S. Pat. Nos. 6,166,063 and 6,107,317 disclose N-substituted 2-cyanopyrrolidines and 4-cyanothiazolidines, respectively. WO 95/15309 discloses various aminoacyl compounds as inhibitors of DPP-IV. WO 01/68603 discloses a class of cyclopropyl-fused pyrrolidine derivatives as inhibitors of DPP-IV. N-substituted 2-cyanopyrrole derivatives as inhibitors of DPP-IV, and pharmaceutical compositions thereof, are taught for the treatment of various metabolic disorders in U.S. Patent Application Publication 2001/0031780.
Beta blockers (sometimes written as β-blockers) or beta-adrenergic blocking agents, beta-adrenergic antagonists, beta-adrenoreceptor antagonists or beta antagonists, are a class of drugs used for various indications. They are particularly for the management of cardiac arrhythmias, cardioprotection after myocardial infarction (heart attack), and hypertension. As beta adrenergic receptor antagonists, they diminish the effects of epinephrine (adrenaline) and other stress hormones. In 1958 the first beta blocker, dichloroisoproterenol, was synthesized by Eli Lilly Laboratories, but it was Sir James W. Black in 1962, who found the first clinically significant use of beta blockers with propranolol and pronethalol; it revolutionized the medical management of angina pectoris and is considered by many to be one of the most important contributions to clinical medicine and pharmacology of the 20th century.